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The Potential Protective Role of GS-441524, a Metabolite of the Prodrug Remdesivir, in Vaccine Breakthrough SARS-CoV-2 Infections.
Zhu, JiaYi; Li, Yuchong; Liang, Jady; Mubareka, Samira; Slutsky, Arthur S; Zhang, Haibo.
  • Zhu J; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON Canada.
  • Li Y; Department of Physiology, University of Toronto, Toronto, ON Canada.
  • Liang J; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada.
  • Mubareka S; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON Canada.
  • Slutsky AS; The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • Zhang H; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON Canada.
Intensive Care Res ; : 1-12, 2022 Nov 09.
Article in English | MEDLINE | ID: covidwho-2119895
ABSTRACT
Cases of vaccine breakthrough, especially in variants of concern (VOCs) infections, are emerging in coronavirus disease (COVID-19). Due to mutations of structural proteins (SPs) (e.g., Spike proteins), increased transmissibility and risk of escaping from vaccine-induced immunity have been reported amongst the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir was the first to be granted emergency use authorization but showed little impact on survival in patients with severe COVID-19. Remdesivir is a prodrug of the nucleoside analogue GS-441524 which is converted into the active nucleotide triphosphate to disrupt viral genome of the conserved non-structural proteins (NSPs) and thus block viral replication. GS-441524 exerts a number of pharmacological advantages over Remdesivir (1) it needs fewer conversions for bioactivation to nucleotide triphosphate; (2) it requires only nucleoside kinase, while Remdesivir requires several hepato-renal enzymes, for bioactivation; (3) it is a smaller molecule and has a potency for aerosol and oral administration; (4) it is less toxic allowing higher pulmonary concentrations; (5) it is easier to be synthesized. The current article will focus on the discussion of interactions between GS-441524 and NSPs of VOCs to suggest potential application of GS-441524 in breakthrough SARS-CoV-2 infections. Supplementary Information The online version contains supplementary material available at 10.1007/s44231-022-00021-4.
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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Topics: Vaccines / Variants Language: English Journal: Intensive Care Res Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Topics: Vaccines / Variants Language: English Journal: Intensive Care Res Year: 2022 Document Type: Article